title: Metabolism of trichloroethene--in vivo and in vitro evidence for activation by glutathione conjugation.
abstract: The metabolism of trichloroethene by glutathione conjugation was investigated in rat liver subcellular fractions and in male rats in vivo. In the presence of glutathione, rat liver microsomes transformed [14C]trichloroethene to S-(1,2-dichlorovinyl)glutathione (DCVG) identified by gas chromatography mass spectrometry after hydrolysis to the corresponding cysteine S-conjugate and chemical derivatisation. In bile of rats given 2.2 g/kg trichloroethene. DCVG was present in concentrations of 5 nmol (7 ml bile collected over 9 h) and identified by thermospray mass spectrometry after HPLC-purification. E- and Z-N-acetyl-dichlorovinyl-L-cysteine (3.1 nmol present in the pooled 24-h urine) were identified by GC/MS after methylation and butylation as urinary metabolites of trichloroethene (2.2 g/kg, orally). The presented results demonstrate that glutathione-dependent metabolism of trichloroethene is a minor route in the biotransformation of this haloalkene in rats. Formation of S-(1,2-dichlorovinyl)-glutathione, processing to S-(1,2-dichlorovinyl)-L-cysteine and metabolism of this S-conjugate by cysteine beta-lyase in the kidney to reactive and genotoxic intermediates may account for the nephrocarcinogenicity observed after long time administration of trichloroethene in male rats.
authors.affiliation: Institut für Toxikologie, Universität Würzburg, F.R.G.
authors.forename: W
authors.initials: W
authors.lastname: Dekant
authors.forename: M
authors.initials: M
authors.lastname: Koob
authors.forename: D
authors.initials: D
authors.lastname: Henschler
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D006710:Homocysteine; C051126:S-(1,2-dichlorovinyl)homocysteine; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; D014241:Trichloroethylene; D005978:Glutathione; D000111:Acetylcysteine